Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus

Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired -at least par...

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Bibliographic Details
Published in:PloS one 2013-03, Vol.8 (3), p.e60357
Main Authors: Westerweel, Peter E, Teraa, Martin, Rafii, Shahin, Jaspers, Janneke E, White, Ian A, Hooper, Andrea T, Doevendans, Pieter A, Verhaar, Marianne C
Format: Article
Language:English
Subjects:
Animals
Antigens, CD34 - analysis
Biology
Blood circulation
Bone marrow
Bone Marrow - physiopathology
Cardiovascular disease
CD34 antigen
Cell Count
Cell culture
Cell growth
Cell Movement
Cell Survival
Cells (biology)
Cells, Cultured
Coculture Techniques
Cytokines
Cytometry
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - physiopathology
Endothelial cells
Endothelial Cells - pathology
Endothelium
Experiments
Flow cytometry
Fluorouracil - metabolism
Granulocyte colony-stimulating factor
Granulocytes
Heart attacks
Hematopoietic stem cells
Hematopoietic Stem Cells - pathology
Human Umbilical Vein Endothelial Cells
Humans
Hyperglycemia
Hyperglycemia - physiopathology
Hypertension
Injection
Insulin
Laboratories
Ligands
Medical prognosis
Medical research
Medicine
Mice
Mice, Inbred C57BL
Nephrology
Progenitor cells
Stem cells
Stem Cells - pathology
Streptozocin
Stroma
Transplants & implants
Vascular endothelial growth factor receptor 2
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Summary:Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired -at least partly- due to dysfunction of the bone marrow stromal compartment. Diabetes was induced in mice by streptozotocin injection. Circulating Sca-1(+)Flk-1(+) EPC were characterized and quantified by flow cytometry at baseline and after mobilization with G-CSF/SCF injections. In vivo hemangiogenic recovery was tested by 5-FU challenge. Interaction within the bone marrow environment between CD34(+) hematopoietic progenitor cells (HPC) and supporting stroma was assessed by co-cultures. To study progenitor cell-endothelial cell interaction under normoglycemic and hyperglycemic conditions, a co-culture model using E4Orf1-transfected human endothelial cells was employed. In diabetic mice, bone marrow EPC levels were unaffected. However, circulating EPC levels in blood were lower at baseline and mobilization was attenuated. Diabetic mice failed to recover and repopulate from 5-FU injection. In vitro, primary cultured bone marrow stroma from diabetic mice was impaired in its capacity to support human CFU-forming HPC. Finally, hyperglycemia hampered the HPC supportive function of endothelial cells in vitro. EPC mobilization is impaired under experimental diabetic conditions and our data suggest that diabetes induces alterations in the progenitor cell supportive capacity of the bone marrow stroma, which could be partially responsible for the attenuated EPC mobilization and reduced EPC levels observed in diabetic patients.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0060357